The development of novel expeditious and efficient methodologies toward the synthesis of biologically significant heterocyclic compounds is planned. The proposed project consists of four major sections. The first section is devoted to the investigation and development of novel cycloisomerization approaches toward monocyclic and fused furans, pyrroles, and thiophenes, and to the development of cascade migration/cyclization methodologies en route to highly substituted heterocycles. The second section is directed toward investigation of the scope of the recently discovered transannulation reaction as a highly attractive modular approach to a variety of diverse heteroaromatic scaffolds. The third section covers transition metal- and Lewis acid-catalyzed C-H functionalization of aromatic and heterocyclic building blocks employing a recently proposed Si-tether motif. The fourth section is aimed at development of new synthetic approaches for the rapid construction of naturally occurring and unnatural heterocyclic molecules of biological importance using methodologies developed in our laboratories. Synthetic targets for the proposed research include various diversely substituted indolizines not easily available by existing techniques, potential selective group V sPLA2 inhibitors; lamellarin D and its analogs; novel lamellarin-campthothecin hybrid pentacyclic scaffolds, potential topoisomerase I inhibitors, and tetra- and pentacyclic heterocyclic skeletons, potential QR2 and aromatase inhibitors. The synthetic part of the proposed work toward selected targets is essential as it may lead to discovery of potent anti-inflammatory and anticancer agents. The methodological part of this proposal toward general and efficient methods for construction and functionalization of diverse fused heterocycles has even broader impact, as upon development, it would dramatically broaden the arsenal of libraries of biologically important molecules available for medicinal chemists and biologists, and will most certainly impact drug discovery research and related health-oriented sciences.